Protein kinases are a large family of proteins that play a pivotal role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. Protein tyrosine kinases may be classified as growth factor receptor (e.g. VEGFR, EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. Receptor tyrosine kinases (RTKs) play a key role in the regulation of cell proliferation, differentiation, metabolism, migration, and survival. Upon ligand binding, they undergo tyrosine phosphorylation at specific residues in the cytoplasmic tail. This leads to the binding of protein substrates and/or the establishment docking sites for adaptor proteins involved in RTK-mediated signal transduction. When unregulated, receptor tyrosine kinases can contribute to the rise of disease states associated with such aberrant kinase activity. Flt3 (FMS-like receptor tyrosine kinase-3), a member of class III tyrosine kinase receptor family, is predominantly expressed in hematopoietic progenitor cells and plays an important role in the pathogenesis of acute myeloid leukemia (AML). Flt3 is expressed in blast cells of most patients with AML including wild-type and two forms of Flt3 mutations. These two mutations identified in the AML patients are internal tandem duplication (ITD) mutations in the juxtamembrane domain and point mutations (TKD) in the activation loop of the TKD. (See, Ryan J. Mattison et al Reviews in Reviews on Recent Clinical Trials, 2007, 2, 135-141). The relapse rates in the Flt3/ITD mutation AML patients are significantly increased and the overall survival rates decreased compared with the AML patients without the Flt3 mutation. So development of a drug of inhibiting Flt3/ITD mutant kinase could provide an effective way to treat AML. Currently more than a dozen known Flt3 inhibitors are being developed and some have shown promising clinical effects against AML (See Levis et al. Int J Hematol, 2005, 82:100-107).
A large portion of DCs are derived from hematopoietic progenitors that express FLT3 receptor (CD135), and stimulation of the receptor via FLT3 ligand either in vivo or in vitro is known to drive expansion and differentiation of these progenitors toward a DC phenotype. Since dendritic cells are the central antigen-presenting cells for initiation of T cell responses to mediate immune response including the autoreactive immune response. Inhibition of FLT3 signaling may thus produce an inhibition of DC-induced stimulation of T cells, thereby inhibiting autoimmune responses. One study shows the Flt3 inhibitor CEP-701, a drug already known to block actions of the growth-promoting FLT3 gene, to be effective in mice model engineered to mimic multiple sclerosis (MS model). Multiple sclerosis is a disease that causes T-cells to destroy the myelin protein sheath around nerves in the central nervous system. This study shows Flt3 inhibitor CEP-701 to be effective in reducing myelin loss in the MS mice model. (See Whartenby et al. PNAS (2005) 102: 16741-16746). The study also shows that hemopoietic cytokines such as Flt3 ligand (a dendritic cell-mobilizing factor) and M-CSF are elevated significantly in the serum of patients with Langerhans cell histiocytosis and systemic lupus erythematosus. Higher level of cytokines correlated with patients having more extensive diseases. The highest serum level of Flt3 and M-CSF were linked with the patients with high risk of extensive skin and/or multisystem involvement, which further implicates Flt3 signaling in the disregulation of dendritic cell progenitors in those autoimmune diseases (See Rolland et al. J. Immunol., 2005, 174:3067-3071).
There is considerable interest in the development of kinase inhibitors for use in cancer therapy. Among them, urea derivatives have been reported to be selective Flt3 inhibitors in Bioorg. Med. Chem. Lett. 10:2051-2054 (2000), WO 99/32106 published 1 Jul. 1999, PCT publication WO 99/32111 published 1 Jul. 1999 and PCT publication WO2007/109120 published in 27 Sep. 2007.